acne vulgaris.pdf

Review ArticleCarrier-Based Drug Delivery System for Treatment of Acne

Amber Vyas, Avinesh Kumar Sonker, and Bina Gidwani

University Institute of Pharmacy, Pandit Ravishankar Shukla University, Raipur 492 010, India

Correspondence should be addressed to Amber Vyas; [email protected] and Bina Gidwani; [email protected]

Received 31 August 2013; Accepted 25 December 2013; Published 9 February 2014

Academic Editors: H. Fujita and C. Schepis

Copyright 2014 Amber Vyas et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Approximately 95% of the population suffers at some point in their lifetime from acne vulgaris. Acne is a multifactorial disease ofthe pilosebaceous unit. This inflammatory skin disorder is most common in adolescents but also affects neonates, prepubescentchildren, and adults. Topical conventional systems are associated with various side effects. Novel drug delivery systems have beenused to reduce the side effect of drugs commonly used in the topical treatment of acne. Topical treatment of acne with activepharmaceutical ingredients (API) makes direct contact with the target site before entering the systemic circulation which reducesthe systemic side effect of the parenteral or oral administration of drug. The objective of the present review is to discuss theconventional delivery systems available for acne, their drawbacks, and limitations. The advantages, disadvantages, and outcomeof using various carrier-based delivery systems like liposomes, niosomes, solid lipid nanoparticles, and so forth, are explained.Thispaper emphasizes approaches to overcome the drawbacks and limitations associated with the conventional system and the advancesand application that are poised to further enhance the efficacy of topical acne formulations, offering the possibility of simplifieddosing regimen that may improve treatment outcomes using novel delivery system.

1. Introduction

Approximately 95% of the population suffers at some point intheir lifetime from acne vulgaris [1]. Papules, pustules, closedandopen comedones, cysts, and scarringmay be seen.Havingacne can give rise to feelings of embarrassment, loss of self-esteem, and depression, as well as physical symptoms (such assoreness and pain) associated with individual lesions. Acneis well known to respond to hormones, both endogenousand exogenous. It is themost common dermatologic disorderaffecting approximately 85% of the teenagers [2, 3] and achronic inflammatory follicular disorder of the skin, occur-ring in specialized pilosebaceous units on the face consistingof the follicular canal with its rudimentary hair, and the groupof sebaceous glands that surround and open on to the follicle[46].

Acne vulgaris can be defined as the most common skindisease, that results in comedos or severe inflammatorylesions in the face, back, and chest with a large numberof sebaceous follicles, and the condition of the disease isassociated with the elevated rate of sebum excretion [7]. Thepathophysiology of acne includes abnormal proliferation anddifferentiation of keratinocytes, increased sebumproduction,

hyper proliferation of Propionibacterium acne, and inflam-matory response initiated by bacterial antigens and cytokines[814]. Figure 1 highlights the difference between a normalskin and the skin with acne. In the skin with acne due tothe excess production of male hormone androgen and oilproducing glands in the face comedone occurs on the face[15]. The closed comedone (whitehead) and ripen comedone(blackhead) are the primary two noninflammatory lesions inacne. These lesions may progress to inflammatory papulesand pustules when the contents rupture. Larger, more painfullesions, such as cysts and nodules, may also develop [16].Theapplication of novel delivery systems to the skin distributesthe topical agent gradually, reduces the irritancy of someantiacne drugs, and shows good efficacy [17].

2. Status of Acne

The severity of acne is rated according to the combinedacne severity classification that classifies acne into mild,moderate, and severe based on the number and type oflesions. Tables 1 and 2 enlist the features of different typesof acne classified according to their general features and

Hindawi Publishing Corporatione Scientic World JournalVolume 2014, Article ID 276260, 14 pageshttp://dx.doi.org/10.1155/2014/276260

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Healthy pore of skin with no infection

Hair Hair and sebum comethrough pore

New skin cellsmade here

Sebaceous gland to bemade sebum (oil)

Sweat gland

Skin with acneA blocked pore, a

blackhead

Infected with

Hair often breaks

Blocked sebum

P. acnes bacteria

Figure 1: Difference between normal skin and skin with acne.

Table 1: Types of acne.

Sr. no Type of acne Features

1 Comedonal(noninflammatory)

Whitehead (closed): a dilated hairfollicle filled with keratin, sebum,and bacteria, with an obstructedopening to the skin.Blackhead (open): a dilated hairfollicle filled with keratin, sebum,and bacteria, with a wide opening tothe skin capped with a blackenedmass of skin debris.

2 Papulopustular(inflammatory)

Papule: small bump less than 5mmin diameter.Pustule: smaller bump with a visiblecentral core of purulent material.

3 Nodular(inflammatory)Nodule: bump greater than 5mm indiameter.

Table 2: Types of acne according to severity.

Sr. no Type of acne Features

1 Mild acneFewer than 20 comedones or fewer than15 inflammatory lesions, or total lesioncount fewer than 30

2 Moderate acne20100 comedones, or 1550inflammatory lesions, or total lesioncount 30125

3 Severe acneMore than 5 nodules, or Totalinflammatory count greater than 50, orTotal lesion count greater than 125

severity [18]. The acne therapeutics market is forecast toshow moderate growth in revenues till 2016. The researchsuggests that the global acne market was worth $2.8 billionin 2009. It is estimated to reach revenues of $3.02 billion by2016 at a compound annual growth rate (CAGR) of 0.7%.Figure 2 highlights the global market forecast of acne. Themoderate increase in revenues is attributed to overcrowding

4

3

2

1

0

2001 2009 2016

Reve

nues

($bn

)CAGR (20012009) = 0.8%

CAGR (20092016) = 0.7%

Global acne market forecast, 20012016

Figure 2: Future forecast of acne.

of the market with generics and the increased acceptanceof alternative therapies such as photodynamic therapy andultraviolet (UV)/blue light therapy. The current market hasseveral products, which act on acne by targeting differentetiologic factors involved in the development of acne [19].Prevalence of acne declines dramatically after the age of25 to 8%. Acne affects between 40 million and 50 millionindividuals in the United States [20]. In India the antiacnemarketwas 130 crores, and growing at the rate of 14% annuallyaccording to the report of 2009, it would perhaps be nowestimated as per the growth standards to somewhere aroundRs. 168.94 or Rs. 169 crores in coming years.

3. Treatment Strategies Used for Acne

Accordingly, no simple recipe for treatment can be given,and treatment options vary with the stage and intensity ofthe disease [2124]. According to the evolution, acne can beclassified as mild, moderate, or severe. Topical treatment isthe first choice in mild and moderate acne, whereas systemictherapy is used to treat severe and moderate cases [25]. Acneis mainly treated in three different ways.

(a) Topical therapy: it includes the use of antibiotics,retinoids, and combination medication. Topical acne

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Table 3: Systemic and hormonal treatment for acne.

(a) Systemic treatment

Antibiotic Name Dose Duration DrawbacksOral antibiotics

Tetracyclines

Tetracycline, Oxytetracycline 250500mg twice daily 46 months Gastrointestinal upset, vaginal candidiasis,decreased complianceDoxycycline 50100mg twice daily 46 months Gastrointestinal upset, photosensitivity

Minocycline 50100mg twice daily 46 months Vertigo, hyperpigmentation of skin and oralmucosa, expensiveLymecycline 150300mg daily 46 months

Macrolides Erythromycin 500mg twice daily 46 monthsGastrointestinal upset, vaginal candidiasis,emergence of resistance of P. acnes

Azithromycin 250mg three times a week 46 months Gastrointestinal upset(b) Hormonal treatment

Name Dose Duration DrawbacksSpironolactone 25100mg twice daily 6 months Menstrual irregularities, contraindicated in pregnancyPrednisone 2.55mg daily Indefinitely Adrenal suppressionDexamethasone 0.1250.5mg daily Indefinitely Adrenal suppressionCyproterone acetate/ethinylestradiol (oral contraceptives) 2mg/3550 g 6 months Vascular thrombosis, melasma, weight gain

Levonorgestrel/ethinyl estradiol 100 g/20g 6 months Vascular thrombosis, melasma, weight gain

medications are usually irritating to the skin; morethan 40% of acne bacteria are insensitive to oralantibiotics and are associatedwith possible severe sideeffects and high cost.

(b) Systemic treatment includes oral antibiotics, reti-noids, and hormonal treatment. Systemic treatmentis indicated for the management of moderate andsevere acne, acne that is resistant to topical treatmentand acne that covers large parts of the body surface.Table 3 highlights the drugs used in systemic andhormonal treatment of acne.

(c) Other treatments include those which are not inabove two categories like resurfacing, dermabrasion,chemical peels, xenografts, heterograft, autograft andfat transplantation. Figure 3 enlists a detailed over-view of all the strategies used in treatment of acnealong with their examples.

4. Conventional Delivery System Used inTreatment of Acne

In earlier days, people all over the world used conven-tional system for treatment of acne. In the 1950s, antibioticsproved to be effective in treating acne because of the anti-inflammatory effects of tetracycline. Retin A, discovered inthe 1960s, was found to fight acne blemishes. Accutane, aform of vitamin A for reducing oil made by skin glands,was introduced as a treatment in the 1980s. Laser treatmentsfor treating acne began in the 1990s and were found to beespecially effective for people suffering from nodular andcystic acne. In the 1970s, tretinoin (original TradeNameRetinA) was found to be effective for acne [26]. This preceded

the development of oral isotretinoin (sold as Accutane andRoaccutane) in 1980 [27]. Also, some antibiotics like minocy-cline were used for treatment for acne [28, 29].

From the nineteenth to twentieth century, almost allthe treatments of acne were based on conventional system.Conventional available dosage forms/delivery system worksby the following four mechanisms, namely, normalizingshedding into the pore to prevent blockage, killing propi-onibacterium acnes, anti-inflammatory effects, and hormonalmanipulation [8, 14]. In spite of various available treatmentsfor acne, many patients fail to respond adequately or developproblematic side effects. Most of the conventional availableformulations usually produce a high incidence of side effectsand symptoms that diminish the patient compliance, com-promising the efficacy of the therapy [3032]. Nevertheless,some of them also lead to skin dryness, peeling and skinirritation, or bacterial resistance [3337]. Table 4 explains theside effects associated with the conventional formulationsused in acne.

To reduce these above mentioned side effects, develop-ment of novel carrier-based drug delivery systems came intoexistence. The application of these novel delivery systemsis advantageous to the skin as it distributes the topicalagent gradually and in some cases has demonstrated theability to reduce the irritancy of some antiacne drugs, yet itmaintains a better efficacy when comparedwith conventionalformulations [17]. The novel drug delivery systems also havethe advantage of penetrating more efficiently into the hairfollicles than do nonparticulate systems, such as conventionalformulations, so long as the size is selected in an appropriatemanner. This provides a high local concentration over aprolonged period [3840].


Table 4: Topical conventional delivery system used for acne.

Conventional delivery system Drug Side effects Reference

Lotion

Benzoyl peroxide Peeling, itching, redness, dryness, burning, and dermatitis [41]Clindamycin Peeling, itching, redness, dryness [42]Tretinoin Erythema, scaling, burning [43]

Erythromycin Erythema, scaling, burning [44]Glycolic acid Itching, rash, pruritus [45]Tretinoin Itching, rash, pruritus [45]

Cream

Adapalene Erythema, scaling, dryness, burning, stinging, irritation, sunburn [46]Tazarotene Erythema, scaling, burning [47]Azelaic acid Itching, rash, pruritus [45]

Tea oil Burning, itching, irritation, stinging [48]Clindamycin Erythema, desquamation [49]

Gel

Salicylic acid Erythema, dryness, dermatitis [41, 50]Erythromycin Dryness, erythema, peeling, dermatitis [44, 51]

Benzoyl peroxide Dryness, erythema, peeling, dermatitis [51]Adapalene Erythema, scaling, dryness, burning, stinging, irritation [46]Dapsone Peeling, itching, redness, burning [52]

Emollient Sodium sulfacetamide-sulfur Dryness, irritation, redness, scaling, stinging, or burning [53]

Oral antibiotics

Tetracycline DoxycyclineMinocycline

ErythromycinAzithromycin

Topicaltreatment

treatmenttreatments

SystemicOther

Oral retinoid

Isotretinoin

Strategies used for treatment of acne

Antibiotics

Azelaic acid Benzoyl peroxide

Clindamycin Dapsone

Erythromycin

Retinoids

TazaroteneTretinoin Adapalene

Combination medicationsAdapalene-benzoyl peroxide

Benzoyl peroxide-clindamycinTretinoin-clindamycin

Hormonal treatment

SpironolactonePrednisone

Dexamethasone

ResurfacingDermabrasionLaser resurfacingChemical peelsXenograftFat transplantation

Figure 3: Treatment strategies used for acne.

5. Novel Drug Delivery System Used toTreat Acne

The efficacy of the antiacne topical drugs using novel carrier-based drug delivery system is well established. The local sideeffects, however, mainly cutaneous irritation, erythema, dry-ness, peeling, and scaling, remain major problems. The anti-acne drug-loaded vesicular and particulate delivery systems

(liposomes, polymericmicrospheres, and solid lipid nanopar-ticles) for topical treatment are advantageous compared toconventional available topical delivery system. The encapsu-lation of antiacne drugs in vesicular and particulate deliverysystems represents an innovative and alternative approach forminimizing the side effects and preserving their efficacy.

Novel drug carriers intended for use in skin diseases areoften designed to increase the load ability of APIs and reduce


Liposome Niosome MicrospongeLiposphere

Novel carrier-based drug delivery system

Microemulsion FullereneSolid lipid nanoparticles

Nanostructuredlipid carriers

Lipid(solid) Hydrophobic

phase

phaseHydrophilic

CosurfactantSurfactant

Figure 4: Novel carrier-based drug delivery system for treatment of acne.

side effect. In dermatotherapy, research on new drug entitiesand drug delivery systems is focused on frequent diseasesoften difficult to treat, in particular acne and psoriasis[54]. For severe manifestations, not infrequent highly activeAPIs, which may also induce major unwanted effects, haveto be prescribed for systemic use. Progress in novel drugdelivery systems may allow the safer use of these agents bythe topical route [55]. The novel carrier systems that areunder investigation for application and treatment of acneinclude liposome, niosome, microsponge, microemulsion,microsphere, SLN, hydrogel, aerosol, fullerenes and so forth[54, 55]. Controlled drug release of these novel carrier-based delivery systems and subsequent biodegradation areessential for developing successful formulations. The drugrelease mechanism of these systems involves desorption ofadsorbed drug, diffusion through the carrier matrix, erosion,and combination of erosion and diffusion method. Alongwith the numerous advantages, novel vesicular carrier systemis associated with some serious disadvantages which restricttheir use: drugs passively may lead to low drug loadingefficiency and drug leakage in preparation, preservation, andtransport in-vivo. Also, the major problem of their stabilityacts as a barrier and limits their use [56]. The novel carrierbased delivery systems are discussed with their advantages,limitations, and suitable examples. Figure 4 shows variouscarrier-based drug delivery systems used in treatment ofacne.

5.1. Liposomes. Liposomes are spherical particles composedof one, several, or multiple concentric membranes [57]. Theyare potent drug delivery systems for treating hair follicle-associated disorders such as acne [58].

5.1.1. Advantage of Liposomal Formulation. After topicalapplication, liposome can improve drug deposition withinthe skin at the site of action, reduces systemic absorption, andminimizes the side effects thereby providing localized effect[59]. They can target the drug to skin appendages in additionand increase the systemic absorption [60]. They can improvethe therapeutic effect of drugs and decrease the adverseeffects. It has been reported that formulations of vesicularsystem lead to better result in the treatment of acne comparedto conventional systemby releasing the drug on targets in skinappendages and these systems aremore suitable for lipophilicdrug [14, 17]. Table 5 enlists the examples of various liposomalformulations used in acne.

5.1.2. Disadvantage of Liposomal Formulation. Themajor dis-advantage of liposomal formulation is related to its stabilityaspect.The stability issue of liposomes remains an area, whichis surrounded by a number of problems; due to the formationof ice crystals in liposomes, the subsequent instability ofbilayers leads to the leakage of entrapped material. Thephysical instability is also faced by liposomes. The oxidationof cholesterol and phospholipids leads to the formulationinstability. Chemical instability indicates the hydrolysis andoxidation of lipids. The destabilization of liposomes is due tothe lipid exchange between the liposomes and HDLs [61].

5.2. Niosomes. Niosomes are unilamellar or multilamellarvesicles wherein an aqueous phase is encapsulated in highlyordered bilayermade up of nonionic surfactant [62].They arenonionic surfactant vesicles by which skin penetration andaccumulation are increased in the superficial skin strata [63].


Table 5: Novel carrier-based delivery system for acne.

Drug Objective Outcomes ReferenceLiposomal formulation

Benzoyl peroxide To improve the antibacterial efficacy ofbenzoyl peroxide

A significant antibacterial effect in theinfundibula against both P. acne andMicrococcaceae was observed as compared to theconventional formulation.

[64]

Clindamycin To improve the stability and penetrability Increased stability and intradermal penetrability [65]

Salicylic acid To reduce associated side effects

Liposomal formulation produced fivefold higherdeposition of drug in skin than the correspondingplain drug solution and conventional gel andreduced skin irritation was observed.

[66]

Tretinoin To improve the stability and thethermodynamic activityIncreased stability and drug retention wereachieved. [67]

Isotretinoin To increase skin targeting and skindeposition and reduce skin irritation.Increase skin targeting, drug deposition anddecrease skin irritation were observed. [68]

Lauric acid To evaluate the antimicrobial activityLauric acid loaded liposomes release the drugdirectly into the bacterial membranes, therebykilling the bacteria effectively.

[14]

Cyproterone acetate To increase percutaneous absorption Better penetration was observed [69]

Finasteride To increase skin permeation, deposition,and stability of the drug.Higher deposition of drug in skin, increasedpermeation and stability were observed. [70]

Tea oil To increase skin permeability of drug.Tea oil liposome disrupted the permeabilitybarrier of cell membrane structures and increasedthe permeability.

[48]

Methylene blue To evaluate the efficacy and tolerability ofliposomes loaded methylene blue.

Liposomal formulation delivered the methyleneblue to sebaceous gland and was effective intreatment of mild-to-moderate acne vulgaris.

[71]

Niosome formulation

Benzoyl peroxide To reduce the associated side effectsNiosomal gel improved the skin retention,therapeutic response and considerably reducedthe adverse symptoms.

[72]

Tretinoin To improve skin drug retention of drug andincrease photostability.

Niosomal formulation improved the cutaneous ortransdermal delivery of a lipophilic tretinoin andincreased photostability.

[63]

Erythromycin To enhance drug retention into skin andimprove stability.

Niosomal gel was significantly more stable ascompared to plain drug gel and marketed gel anddrug retention was increased.

[72]

Microsponge formulationBenzoyl peroxide To reduce skin irritation. Controlled release and reduced skin irritation [73]

Tretinoin To reduce cutaneous side effect Controlled release of tretinoin with reducedcutaneous side effects. [74]

Microemulsion formulation

Tretinoin To increase skin permeation and skinretention.

Novel microemulsion increases tretinoinpenetration through skin and maximum amountof drug retained as compare to plain drug insolution, gel and marketed preparation.

[75, 76]

Retinoic acid To increase lipophilicity and skinpermeability.

The O/Wmicro emulsions containing a counterion increased the skin permeability andlipophilicity of drug.

[77]

Microsphere formulation

Benzoyl peroxide To reduce skin irritation on topicaltreatment.

Cream containing microspheres of benzoylperoxide offered favorable efficacy with a very lowpotential for irritation.

[78]

TretinoinTo reduce cutaneous irritation, includingerythema, peeling, dryness, burning, anditching.

Microsphere formulation reduced local sideeffects and sustained release was achieved. [79]

All trans retinoic acid To control the release of drug. Controlled release of drug was produced byencapsulation of drug into the microsphere. [80]


Table 5: Continued.

Drug Objective Outcomes ReferenceSolid lipid nanoparticles formulation

TretinoinTo evaluate the potential of a lipophilic drugwith respect to primary skin irritation, invitro occlusivity and skin permeation.

Lesser skin irritancy, greater skin tolerance,occlusivity, slow drug release, and increasedpermeability were observed with the developedtretinoin loaded SLN-based gels more than thecommercial product.

[81]

Isotretinoin To evaluate skin penetrationSLN loaded with isotretinoin significantlyincreased the accumulative uptake of drug intothe skin and enhanced the skin permeation.

[82]

All trans retinoic acid To produce comedolytic effect and reduceskin irritation.SLN produced comedolytic effects and epidermalthickening with reduced skin irritation. [73]

Sphingosome To increase skin permeation of drug. Sphingosome SLN enhanced the permeation ofthe drug through the skin to acne lesion. [83]

Cyproterone acetate(CPA)

To reduce side effect and improve skinpenetration and absorption.

CPA attached to SLN increased skin penetrationat least four-fold over the uptake from cream andnanoemulsion. Incorporation of drug into thelipid matrix of NLC resulted in a 2 to 3 foldincrease in CPA absorption.

[84]

Triclosan To increase stability, skin retention andpermeability.

Triclosan nanoparticle increased the stability andshowed higher retention and permeability thanconventional cream formulation.

[85]

Hydrogel formulation

Triclosan To increase the permeability through skin. Triclosan permeability was increased by usingtranscutol as a permeation enhancer. [86]

Tretinoin To increase release permeation and reduceskin irritation of tretinoin.

The complexation of tretinoin withdimethyl--cyclodextrin overcome the drugs lowwater solubility thereby increasing drug releaseand enhanced the drug permeation by promotingskin absorption and alleviate drug inducing localirritation.

[87]

Aerosol foams formulation

Juniper oil To reduce the volatility and maintainantibacterial activity.

Juniper oil solid lipid microparticles substantiallymaintain the oil loaded inside their lipidicstructure, reducing its volatility and retaining itsantibacterial activity.

[88]

5.2.1. Advantage of Niosomal Formulation. Niosomes areone of the promising drug delivery systems in the treat-ment of skin disorders. When applied topically, niosomescan enhance the residence time of drug in the stratumcorneum and epidermis, while systemic absorption of thedrug can be reduced [8992]. They also increase the hornylayer properties by reducing transepidermal water loss andincreasing the smoothness via replenishing lost skin lipids[63, 93, 94]. Table 5 describes the niosome formulationsand their outcomes for treatment of acne. Both niosomesand liposomes are equiactive in drug delivery potential andboth increases the drug efficacy as compared with that offree-drug. Niosomes are preferred over liposomes becausethe former exhibit high chemical stability and economy.One of the reasons for preparing niosomes is that theyassume higher chemical stability of the surfactants thanthat of phospholipids, which are used in the preparation ofliposomes. Due to the presence of ester bond, phospholipidsare easily hydrolysed [95].

5.2.2. Disadvantages of Niosomes. Although niosomes aresuperior to liposomes, they have some stability problemsassociated with them such as physical stability of fusion,aggregation, sedimentation, and leakage on storage. Themajor issue is the hydrolysis of encapsulated drugs whichlimits the shelf life of the dispersion in niosomes [96].

5.3. Microsponges. Microsponges are uniform, spherical, andporous polymeric delivery system having size range of 5300 m [97, 98]. They represent a myriad of interconnectingvoids within a noncollapsible structure with a large poroussurface loaded with the active agent [54]. It is a microscopicsphere capable of absorbing skin secretions, therefore reduc-ing the oiliness of the skin.

5.3.1. Advantage of Microsponge. Topical agents are a main-stay in cosmetics and the treatment of dermatologicaldisorders. Microsponge delivery system when applied tothe skin, the release of drug can be controlled through


diffusion or other variety of triggers, including rubbing,moisture, pH, friction, or ambient skin temperature [99].Controlled release of drug from a delivery system to theskin could reduce the side effect while reducing percutaneousabsorption. Microsponges are capable of absorbing skinsecretions, therefore reducing oiliness and shine from theskin. Microsponge polymers possess the ability to load awide range of actives providing the benefits of enhancedproduct efficacy, mildness, tolerability, and extended wearto a wide range of skin therapies [100, 101]. As comparedto liposomes, which suffer from lower payload, difficultyin formulation, limited chemical stability, and microbialinstability, the microsponge system in contrast is stable overrange of pH 1 to 11 and temperature up to 130C; compatiblewith most vehicles and ingredients, self-sterilizing as averagepore size is 0.25 m where bacteria cannot penetrate, higherpayload (50 to 60%), still free flowing, and cost effective[9, 10]. One of the most suitable examples is the microspongeof benzoyl peroxide, for topical delivery which maintainedefficacy with decreased skin irritation and sensitization [102].Table 5 shows the variousmicrosponge delivery systems usedfor treatment of acne.

5.4. Microemulsion and Nanoemulsion. Microemulsions aretransparent dispersions of oil and water having droplet sizeof 100 nm in diameter stabilized by an interfacial film ofsurfactant and cosurfactant molecules [103, 104]. Surfactantand cosurfactant are used to decrease the interfacial tensionbetween oil and water phase [47].

5.4.1. Advantage of Microemulsion. (Co-)surfactant acts aspenetration and occlusivity enhancer that improves skin pen-etration to variable degrees [105]. In microemulsion, activeagents are solubilised and thus they are available for quickpenetration into the skin. Nanoemulsions (oil in water orwater in oil formulation) are characterized by the dispersionof very small sized droplets whenmixed.They are appropriatecarrier for the transport of lipophilic compounds into theskin and are considered as ideal vehicle for use in acne.This increases the penetration of active component insidethe lipophilic environment of the pilosebaceous unit. Theyalso produce additional therapeutic effects like increased skinhydration and viscoelasticity. Table 5 highlights the variousmicroemulsion formulations used in acne.

5.5. Microspheres. It is well said poor adherence is directlylinked to poor treatment results and patient dissatisfaction[106]. Irritation commonly associated with topical thera-pies is one of the most significant factors contributing tolack of adherence and therefore therapeutic withdrawal.Microspheres are small spherical shaped particles made ofbiodegradable polymer and is filled with drug substance thatis dispersed homogenously throughout the core and thesespheres when degraded, releases the drug for desired time.These microspheres act as a reservoir system for the activeagent [40, 54]. Microencapsulation technique is mainly usedfor the preparation of the microspheres which provide finecoating of inert, natural, and synthetic polymeric materialsdeposited around solid and liquid micronized particles [42].

5.5.1. Advantage ofMicrospheres. Microspheres when admin-istered to the skin, the amount of free drug in the formulationpenetrates into the epidermis and is compensated by drugrelease from the microspheres. This system offers sustaineddrug delivery without overloading the epidermis or resultingan increase in the transdermal penetration [40, 42]. Table 5enlists the microsphere formulations of drugs used in treat-ment of acne. Microsphere formulation of topical tretinoinand BPO (benzoyl peroxide) currently on the market hasdemonstrated good efficacy and tolerability and is expectedto encourage adherence and long-term therapeutic benefit.Microsphere encapsulation protects the stability of drugs andmakes them photostable. Furthermore, microspheres appearto absorb sebum from the skins surface, reducing oiliness,which is a common complaint among acne patients [107].

5.6. Solid Lipid Nanoparticles (SLNs). Solid lipid nanoparti-cles (SLN) were introduced in the year 1991 and they embodyan alternative carrier system to tradition colloidal carrierssuch as emulsions, liposomes, and polymeric carriers. Solidlipid nanoparticles (SLNs) are particles made from solidlipids with a mean diameter between approximately 50 and1000 nm, which are normally stabilized by lecithin [108, 109].The reasons for the ever-increasing applications of lipidbased system are manyfold and include the following: lipidsenhance the oral bioavailability and reduce plasma profilevariability, better characterization of lipoid excipients, andan improved ability to address the key issues of technologytransfer and manufacture scale-up.

5.6.1. Advantage of SLN. The release rate of the drug fromSLNs depends on the presence of the drug in the solid lipidmatrix. If the drug is localized only in the outer shell, burstrelease will be obtained and not controlled release. If thedrug is homogeneously distributed within the lipid matrix,however, controlled release can be achieved [110, 111]. Table 5enlists the SLN-based formulations for acne.

5.6.2. Disadvantages of SLN. Some of the parameters, whichhinder the use of SLN, are particle growth, unpredictablegelation tendency, and unexpected dynamics of polymerictransitions.

5.7. Hydrogel. Hydrogels are the network of polymer chainsthat are water-insoluble, and sometimes they are found asa colloidal gel in which water is the dispersion medium.Hydrogels are superabsorbent natural or synthetic polymers[86, 112].

5.7.1. Advantage of Hydrogel. Hydrogels are three dimen-sional, hydrophilic networks that hold large amount of wateror biological fluids, similar to biological tissues. Becauseof this unique property, hydrogels show good biomedicalapplications. By tuning, the physicochemical properties ofthe hydrogels suitable modulated drug delivery system aregenerated [112]. Table 5 explains the objective of hydrogelformulation of triclosan and tretinoin.

5.8. Aerosol Foams. The products packed under pressure andthat contain therapeutic active ingredients, which are released


upon activation of an appropriate valve system, are calledaerosols. These foams are suitable for topical application tothe skin and local application into the nose, lungs, andmouth.Aerosol foams are one of the novel drug delivery systemused in treatment of acne vulgaris. Foams are preferred forapplication on large hairy surfaces like the chest, back, and inthe face as cleansers due to easiness of application [113, 114].

5.8.1. Advantage of Aerosol Foams. The physicochemicalcharacteristics of vehicle base of the aerosol foamare the sameas those of the conventional vehicles like creams, lotions, andgels, having a liquid or semisolid consistency, but aerosolfoammaintains desirable properties such asmoisturizing fastdrying effects or higher drug bioavailability. Gas pressurizedsystem is used to dispensed the aerosol foam [113, 114]. Table 5explains the objective of aerosol formulation of salicylic acidand benzoyl peroxide.

5.9. Fullerenes. Like hollow sphere, fullerenes are moleculescomposed of carbon. It is reported that when fullerenesare exposed to the skin, they migrate through the skinintercellularly, as opposed tomoving through cells.Therefore,a fullerene could be used to trap active compounds andthen release them into the epidermis once they are appliedon the skin. Moreover, fullerenes, themselves, are thought tobe potentially potent antioxidants. Literature on fullerenesproved that they can be tolerated and can hold substantialpromise in dermatologic and cosmetic applications.

5.9.1. Advantage of Fullerenes. Fullerenes are an excellentantioxidant and a safe material for the suppression of acnevulgaris.This occurred by the inhibition of lipid peroxidationbecause of fullerenes antioxidant activity and the suppres-sion of sebum production without the production of anyside effects. Thus, fullerenes can serve as novel carriers fortreatment of acne.

5.10. Lipospheres. Lipospheres are lipid-based encapsula-tion system, used for topical drug delivery of variousmedicaments. Lipospheres consists of water dispersible solidmicroparticles, which have diameter ranging from 0.1 to100 m. In liposphere, solid hydrophobic fat core is stabilizedby a layer of phospholipid molecules embedded in their sur-faces, which are a potential group of penetration enhancers[115119].

5.10.1. Advantage of Lipospheres. Better physical stability,high dispersability in aqueousmedium and prolonged releaseof various types of drugs including anti-inflammatory com-pounds, local anesthetics, antibiotics, and anticancer agentsare possible using this type of system [120122].

5.11. Polymers. Polymers are large molecules, which consistof repeating structural units of monomers connected bychemical covalent bonds. In dermatology, the new acrylicacid polymer turns into gel in presence of water by trap-ping water into microcells. A stable gel-like formulationcontaining hydrophilic compound as solution and lipophiliccompound in the form of suspension is easy to use, and itreleases the active compound after single application. For

example, an antiacne formulation that combines clindamycin(1%) and benzoyl peroxide (5%) utilizes this novel polymer-based gel technology and provides excellent tolerability andefficacy.

Despite the availability of numerous effective medicaltherapies for acne vulgaris, issues of safety, compliance, andless than ideal efficacy help drive the search for alternativetreatments for this exceedingly common clinical problem.Recently, scientists have developed effective vaccine for P.acnes-associated inflammatory acne, consisting of a cell wall-anchored sialidase of P. acnes or killed-whole organism of P.acnes [123, 124]. They also hope to develop a future bacterialtherapy for overcoming problems seen with the continuoususe of antibiotics such as a building up a bacteria resistance.These scientists of the 21st century are convinced that acneis not due to dirt and that scrubbing skin can lead to worseproblems.Therefore, in the future, it is possible to explore theuse ofmicro- and nanocarrier-based drug delivery systems inadvanced form with increase in effectiveness for treatment ofacne.

5.12. Nanostructured Lipid Carriers. Nanostructured lipidcarriers are smarter second-generation drug carrier systemshaving solid matrix at room temperature. This carrier sys-tem is usually made up of physiological, biodegradable,and biocompatible lipid materials and surfactants and isaccepted by regulatory authorities for application in differentdrug delivery systems. NLCs exhibit superior advantagesover other colloidal carriers like nanoemulsions, polymericnanoparticles, liposomes, SLN, and so forth and thus they arebeen explored to more extent in drug delivery.

5.12.1. Advantages of NLCs. The unique set of advantages ofNLCs includes enhanced drug loading capacity, preventionof drug expulsion, and more flexibility for modulation ofdrug release. For example, Zhou, prepared adapalene (aretinoid antiacne drug) loaded nanostructured lipid carriersfor topical use. These NLCs were able to accumulate in hairfollicles and improve the follicular delivery of adapalene.Thus, NLCs could be promising carriers for topical deliveryof antiacne drugs.

5.13. Cyclodextrin Based Carriers. Cyclodextrins (CDs) area family of cyclic oligosaccharides derived from starch con-taining six (-CD), seven (-CD), eight (-CD), or more(-1,4)-linked -D-glucopyranose units. They take the shapeof a truncated cone or torus instead of a perfect cylinderbecause of the chair conformation of the glucopyranose units.These versatile, pharmaceutical-material CDs are classifiedinto hydrophilic, hydrophobic, and ionic derivatives [125].Cyclodextrin complexation is a well known technique forenhancing the solubility and stability of drug, sustaining therelease and minimizing the photo degradation of drug. Inparticular, the focus of investigation involves the combinationof vesicular approach with cyclodextrin complexation (dualapproach) which would help in increasing the solubility, skinpermeation, and deposition and reducing the photodegra-dation of drugs. Nowadays drug-cyclodextrin-vesicles dualcarrier approach for targeting of antiacne agent to skin is


used. For example, Kaur et al. prepared isotretinoin-hydrox-ypropyl--cyclodextrin (HP--CD) inclusion complex andencapsulated this complex in elastic liposomes and studiedthe effect of dual carrier approach on skin targeting [68].The isotretinoin elastic liposomal formulation possessedgreat potential for skin targeting, prolonging drug release,reduction of photodegradation, reducing skin irritation, andimproving topical delivery.

6. Conclusion

Adolescent stage is a complex life cycle characterized bymany striking biological, psychological, physical, and socialchanges. It is a labile stage where most self-esteem devel-opment occurs, whereas low self-esteem is associated withanxiety, depression, and increased reports of general psy-chiatric morbidities. The physical changes of acne may havenegative effect on the psychology, self-esteem, and qualityof life of adolescents. Although many traditional oral andtopical medical agents have been demonstrated to be effectivein the treatment of acne, the prevalence of the diseaseand its frequently resistant nature make the developmentof alternative therapies highly desirable. There has beensignificant progress over the past few years, but not alldevelopments can be universally applied. An effective topicalformulationmust provide stability and enhanced penetrationof active ingredients at optimal concentrations for efficacyand it should be acceptable and cheaper and should not addside effects of its own.The encapsulation of antiacne drugs in(vesicular and particulate) carrier delivery systems representsan innovative alternative to minimize the side effects, whilepreserving their efficacy. They can enhance the dermal andtransdermal use and can alter the skin penetration. Thepenetration rate can increase or decrease depending on thenature of the active agent and the preparation. Improveduptake is often linked with higher efficacy and minimizesthe side effect. The capacity of these systems can providecontrolled release to improve the drug penetration into skinor even into the pilosebaceous unit. If the concentrationof the active pharmaceutical ingredient is adjusted, localtolerability can be improved. Currently, only very few drugsbased on microsized or nanosized application systems havebeen approved for topical use and introduced into themarket.Much progress has been made to improve the performanceof antiacne care products in recent years. These new formu-lations based on carrier system provide efficacy, tolerability,compliance, and cosmetic acceptability. In coming future, theuse of cyclodextrin based carriers and their delivery systemwill be more beneficial as it covers dual approach comprisingthe advantage of both system and lead to development of safeand effective formulation, which would be cost effective, andsave time and labor.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

The authors are thankful to Director, University Institute ofPharmacy, Pt Ravishankar Shukla University Raipur, Chhat-tisgarh for providing necessary infrastructural facilities. Theauthors are also thankful to Chhattisgarh council of scienceand technology, CCOST/MRP/2012 Endt. No. 1926 and Uni-versity Grant Commission, UGC-MRP F. No. 42-706/2013(SR) for providing financial assistance relating to this work.Authors also want to thank library of Pt. Ravishankar ShuklaUniversity for providing e-resources available through UGC-INFLIBNET.

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